Cancer is recognized as the second leading cause of death worldwide. When the balance between cell proliferation and cell death is disrupted, the ensuing aberrant proliferation leads to tumor growth. Cancer treatment is still largely achieved through the use of chemo and radiotherapy, both of which cause various side-effects. Treatments which are tailored for specific tumors with minimum side-effects are the ultimate goal of cancer therapy. For certain types of tumors which express labile anti-apoptotic proteins, repression of cellular transcription could be useful. Compounds that are global transcriptional inhibitors are an attractive therapeutic option. A few examples of this class of compounds include 5,6-Dichloro-1-β-ribofuranosylbenzimidazole (DRB) and Flavopiridol.
In eukaryotes, mRNA synthesis is mediated by concerted action of a number of factors, chief among them being the RNA polymerase II [1]. The process of RNA polymerase II transcription consists of the pre-initiation, initiation and the elongation stages [2]. Several inhibitors of transcription are known, which work by blocking one or more of these stages. For example, actinomycin D, which is both a transcriptional inhibitor and a DNA damage agent, intercalates within the DNA and thus inhibits the initiation stage of transcription [3]. Flavopiridol and DRB target the elongation stage of transcription, by inhibiting positive transcription elongation factor b (P-TEFb, a cyclin-dependent protein kinase (CDK) of Cdk9/Cyclin T1) [4-6], whose phosphorylation of RNA polymerase II is essential for this stage. α-Amanitin, on the other hand, binds directly to RNA polymerase II, which leads to inhibition of both initiation and elongation stages [7-10].
General transcriptional inhibitors may be useful in cancer therapies and, in some instances, have been shown to work as anti-viral agents [11, 12]. For example, flavopiridol is a very efficient inducer of apoptosis in malignant cells and it also potentiates lethal effects of other cytotoxic drugs [11, 13]. In addition, it inhibits cell migration and displays potent anti-angiogenic activity [14, 15]. Specifically, this class of drugs may be useful against tumors that express labile anti-apoptotic proteins due to their ability to downregulate proteins of short half-life [11]. Understandably, these drugs may also act synergistically with certain factors such as tumor necrosis factor-α (TNF-α), which is known to transcriptionally induce anti-apoptotic proteins [16].